This invention relates to metal-containing, therapeutic, antimicrobial, and antifungal compounds. More particularly, this invention relates to metal complexes of N-heterocyclic carbenes and their use as antimicrobial agents, antifungal agents and radiopharmaceutical compositions.
Silver has long been used for its antimicrobial properties. This usage predates the scientific or medical understanding of its mechanism. For example, the ancient Greeks and Romans used silver coins to maintain the purity of water. Today silver is still used for this same purpose by NASA on its space shuttles. Treatment of a variety of medical conditions using silver nitrate was implemented before 1800. A 1% silver nitrate solution is still widely used today after delivery in infants to prevent gonorrheal ophthalmia. Since at least the later part of the nineteenth century, silver has been applied in a variety of different forms to treat and prevent numerous types of bacteria related afflictions.
Other treatments, such as the application of silver foil to post surgical wounds to prevent infection survived as a medical practice into the 1980's in Europe, and silver nitrate is still used as a topical antimicrobial agent. In the 1960's the very successful burn treatment silver complex, silver sulfadiazine, shown in formula 1 below, was developed. Commercially known as Silvadene® Cream 1%, this complex has remained one of the most effective treatments for preventing infection of second and third degree burns. Silver sulfadiazine has been shown to have good antimicrobial properties against a number of gram-positive and gram-negative bacteria. It is believed that the slow release of silver at the area of the superficial wound is responsible for the process of healing. Studies on surgically wounded rats have shown the effectiveness of both silver nitrate and silver sulfadiazine to aid in the healing process. By using these common silver antimicrobial agents, inflammation and granulation of wounds were reduced, although the complete mechanism for these phenomena is not understood.

Recently developed silver-coating techniques have lead to the creation of a burn wound dressing called Acticoat. The purpose of this dressing is to avoid adhesion to wounds while providing a barrier against infection. Some clinical trials have also demonstrated the ease of removal of the dressing in contrast to conventional wound dressings treated with silver nitrate. Acticoat has shown an increase in antibacterial function over both silver nitrate and silver sulfadiazine. Acticoat is made up of nanocrystalline silver particles. Antibiotic-resistant strains have developed rarely to both silver nitrate and silver sulfadiazine but not to nanocrystalline silver. The broader range of activity of nanocrystalline silver is apparently due to the release of both silver cations and uncharged silver species. Due to the continuing emergence of antibiotic resistant strains of infectious agents, a need exists for novel antibiotics.
Metal compounds have also played a significant role in other therapeutic applications. One example of the usefulness of the metals can be seen in the field of radiopharmaceuticals. The use of radiation therapy to destroy tumor cells is well known, but tumors can reappear after therapy. Hypoxic cells within the tumor are 2.5 to 3 times more resistant to X-ray radiation than other tumor cells. For this reason, these cells are more likely to survive radiation therapy or chemotherapy and lead to the reappearance of the tumor. Targeting of radionuclides to hypoxic cells will serve as a method to visualize them.
Complexes of γ-ray emitters such as 99Tc are extremely useful as imaging agents, and therapeutic radiopharmaceuticals like 89Sr, 153Sm, 186Re and 166Ho are important in the treatment of bone tumors. Rh-105 emits a gamma ray of 319 keV (19%) that would allow in vivo tracking and dosimetry calculations. Many more radioactive nuclei can be harnessed by using the entire periodic table to construct diagnostic or therapeutic agents.
Urinary tract infections (UTIs) represent the second most common infectious disease in the United States and are associated with substantial morbidity and medical cost. These infections, including cystitis and pyelonephritis, are most commonly caused by uropathogenic Escherichia coli (UPEC). Patients with neurogenic bladder, indwelling urinary catheters, or vesicoureteral reflux, as well as otherwise healthy women, experience recurrences; repeated infections of the urinary tract can lead to renal scarring and chronic kidney disease (CKD). Current preventive and therapeutic strategies fail to address the problem of recurrent UTIs. Recent work in the murine cystitis model has unveiled new paradigms regarding the pathogenesis of UTI. Long thought to be strictly extracellular pathogens, UPEC have been shown to invade superficial epithelial cells lining the bladder and to establish large collections, termed intracellular bacterial communities (IBCs), within these cells. From there, UPEC form a quiescent reservoir within bladder tissue that is sequestered from host defenses, resists antibiotic therapies, and can serve as a nidus for recurrence.
The rapid rise in antimicrobial resistance rates among pathogenic strains renders treatment and prophylactic regimens for UTI increasingly difficult. For this reason, it is desired to interrogate the utility of silver carbenes as novel antimicrobials within the urinary tract. The antimicrobial properties of silver have been recognized for centuries, and there is recent resurgence of interest in this metal as a biocide. Though silver-impregnated urinary catheters have reduced the incidence of UTI in certain populations (e.g., patients with indwelling catheters), novel strategies are needed to prevent recurrent UTI in other patients (e.g., healthy women and patients with functional and anatomic abnormalities of the urinary tract). Organometallic complexes of silver with N-heterocyclic carbenes (NHCs), have been designed and synthesized. The primary advantage of these silver carbenes (SCs) over existing silver compounds is their stability and water solubility.
The usefulness of complexes of radioactive metals is highly dependent on the nature of the chelating ligand. A successful metal drug must both target a specific tissue or organ as well as rapidly clear from other tissues. In addition, for both imaging and tumor treatment, the target organ or tissue must have optimal exposure to the radiopharmaceutical. Therefore, there is a need for novel ligand systems designed to bind radioactive metals.